Prodrugs of amino quinazoline kinase inhibitor

ABSTRACT

Disclosed are compounds having the formula: 
     
       
         
         
             
             
         
       
     
     wherein X is as defined herein, and methods of making and using the same.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel prodrugs of a quinazolyl aminethat inhibits RIP2 kinase and methods of making and using the same.Specifically, the present invention relates to novel prodrugs of2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethanol.

2. Background of the Invention

Receptor interacting protein-2 (RIP2) kinase, which is also referred toas CARD3, RICK, CARDIAK, or RIPK2, is a TKL family serine/threonineprotein kinase involved in innate immune signaling. RIP2 kinase iscomposed of an N-terminal kinase domain and a C-terminalcaspase-recruitment domain (CARD) linked via an intermediate (IM) region((1998) J. Biol. Chem. 273, 12296-12300; (1998) Current Biology 8,885-889; and (1998) J. Biol. Chem. 273, 16968-16975). The CARD domain ofRIP2 kinase mediates interaction with other CARD-containing proteins,such as NOD1 and NOD2 ((2000) J. Biol. Chem. 275, 27823-27831 and (2001)EMBO reports 2, 736-742). NOD1 and NOD2 are cytoplasmic receptors whichplay a key role in innate immune surveillance. They recognize both grampositive and gram negative bacterial pathogens and are activated byspecific peptidoglycan motifs, diaminopimelic acid (i.e., DAP) andmuramyl dipeptide (MDP), respectively ((2007) J Immunol 178, 2380-2386).

Following activation, RIP2 kinase associates with NOD1 or NOD2 andappears to function principally as a molecular scaffold to bringtogether other kinases (TAK1, IKKα/β/γ) involved in NF-κB andmitogen-activated protein kinase activation ((2006) Nature ReviewsImmunology 6, 9-20). RIP2 kinase undergoes a K63-linkedpolyubiquitination on lysine-209 which facilitates TAK1 recruitment((2008) EMBO Journal 27, 373-383). This post-translational modificationis required for signaling as mutation of this residue prevents NOD ½mediated NF-kB activation. RIP2 kinase also undergoesautophosphorylation on serine-176, and possibly other residues ((2006)Cellular Signalling 18, 2223-2229). Studies using kinase dead mutants(K47A) and non-selective small molecule inhibitors have demonstratedthat RIP2 kinase activity is important for regulating the stability ofRIP2 kinase expression and signaling ((2007) Biochem J404, 179-190 and(2009) J. Biol. Chem. 284, 19183-19188).

Dysregulation of RIP2-dependent signaling has been linked toautoinflammatory diseases. Gain-of-function mutations in theNACHT-domain of NOD2 cause Blau Syndrome, early-onset sarcoidosis, apediatric granulomateous disease characterized by uveitis, dermatitis,and arthritis ((2001) Nature Genetics 29, 19-20; (2005) Journal ofRheumatology 32, 373-375; (2005) Current Rheumatology Reports 7,427-433; (2005) Blood 105, 1195-1197; (2005) European Journal of HumanGenetics 13, 742-747; (2006) American Journal of Ophthalmology 142,1089-1092; (2006) Arthritis & Rheumatism 54, 3337-3344; (2009) Arthritis& Rheumatism 60, 1797-1803; and (2010) Rheumatology 49, 194-196).Mutations in the LRR-domain of NOD2 have been strongly linked tosusceptibility to Crohn's Disease ((2002) Am. J. Hum. Genet. 70,845-857; (2004) European Journal of Human Genetics 12, 206-212; (2008)Mucosal Immunology (2008) 1 (Suppl 1), S5-S9. 1, S5-S9; (2008)Inflammatory Bowel Diseases 14, 295-302; (2008) Experimental Dermatology17, 1057-1058; (2008) British Medical Bulletin 87, 17-30; (2009)Inflammatory Bowel Diseases 15, 1145-1154 and (2009) Microbes andInfection 11, 912-918). Mutations in NOD1 have been associated withasthma ((2005) Hum. Mol. Genet. 14, 935-941) and early-onset andextraintestinal inflammatory bowel disease ((2005) Hum. Mol. Genet. 14,1245-1250). Genetic and functional studies have also suggested a rolefor RIP2-dependent signaling in a variety of other granulomateousdisorders, such as sarcoidosis ((2009) Journal of Clinical Immunology29, 78-89 and (2006) Sarcoidosis Vasculitis and Diffuse Lung Diseases23, 23-29) and Wegner's Granulomatosis ((2009) Diagnostic Pathology 4,23).

A potent, selective, small molecule inhibitor of RIP2 kinase activitywould block RIP2-dependent pro-inflammatory signaling and therebyprovide a therapeutic benefit in autoinflammatory diseases characterizedby increased and/or dysregulated RIP2 kinase activity. InternationalPatent Application PCT/US2012/051247 (WO2013/025958) describes a seriesof quinazolyl amine compounds which are indicated as inhibitors of RIP2kinase. Specifically disclosed in that application is the compound2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethanol.

As is known in the art, the bioavailability of compounds within astructural class is difficult to predict. Relatively minor structuralmodifications often have a large impact on the absorption of a compound,its blood level concentrations and/or its half-life. As a consequence,structurally related compounds that have very good in vitro potency mayvary in therapeutic effectiveness. The viability of a putative medicinalagent may be attenuated by poor oral bioavailability.

Prodrugs are bioreversible derivatives of drug molecules that undergo anenzymatic and/or chemical transformation in vivo to release the activeparent drug, which can then exert the desired pharmacological effect. Inboth drug discovery and development, prodrugs have become an establishedtool for improving physicochemical, biopharmaceutical, orpharmacokinetic properties of pharmacologically active agents. Incertain cases, identification of an appropriate prodrug may be necessaryin order to obtain an effective orally-administered therapeutic.

SUMMARY OF THE INVENTION

The invention is directed to quinazolyl amine compounds according toFormula (I):

wherein:

X is selected from the group consisting of:

R^(1a) and R^(1b) are each independently H, (C₁-C₄)alkyl, or—CH₂OCO₂(C₁-C₄)alkyl;

or R^(1a) and R^(1b) together represent —(CH₂)₂— or —(CH₂)₃—;

R^(2a), R^(2b), R^(3a), and R^(3b) a are each independently H or(C₁-C₄)alkyl, wherein said (C₁-C₄)alkyl is optionally substituted by—CO₂(C₁-C₄)alkyl;

or R^(2a) and R^(2b) together represent —(CH₂)₄—, —(CH₂)₅—,—(CH₂)₂O(CH₂)₂—, —(CH₂)₂NH(CH₂)₂—, or —(CH₂)₂N(CH₃)(CH₂)₂—;

or R^(3a) and R^(3b) together represent —(CH₂)₄—, —(CH₂)₅—,—(CH₂)₂O(CH₂)₂—, —(CH₂)₂NH(CH₂)₂—, or —(CH₂)₂N(CH₃)(CH₂)₂—;

or R^(2b) and R^(3b) together represent —(CH₂)₂— or —(CH₂)₃—;

R⁴ is —OH or —NH₂;

R⁵ is (C₁-C₆)alkyl, —O(C₁-C₄)alkyl, —NR⁶R⁷, or 5- or 6-memberedheterocycloalkyl, wherein said (C₁-C₆)alkyl is substituted by —OH,—OP(═O)(OH)₂, —NH₂, or —NHCO(C₁-C₄)alkyl, wherein the (C₁-C₄)alkyl groupof said —NHCO(C₁-C₄)alkyl is optionally substituted by —NH₂, and whereinsaid 5- or 6-membered heterocycloalkyl is optionally substituted, one ortwo times independently, by (C₁-C₄)alkyl, oxo, or an additional 5- or6-membered heterocycloalkyl; and

R⁶ and R⁷ are each independently H or (C₁-C₄)alkyl;

or a salt thereof

The compounds according to Formula (I), or salts, particularlypharmaceutically acceptable salts, thereof, are upon administration to ahost, converted into an inhibitor of RIP2 kinase. This invention isparticularly directed to quinazolyl amine compounds according to Formula(I), or a salt thereof, particularly a pharmaceutically acceptable saltthereof, or a hydrate thereof, which, upon administration to a host, areconverted into an inhibitor of RIP2 kinase.

Accordingly, the present invention is also directed to a method ofinhibiting RIP2 kinase which method comprises administering to a host acompound according to Formula (I), or a salt, particularly apharmaceutically acceptable salt, thereof.

The invention is further directed to a method of treating a RIP2kinase-mediated disease or disorder which comprises administering atherapeutically effective amount of a compound according to Formula (I),or a salt, particularly a pharmaceutically acceptable salt thereof, to apatient (a human or other mammal, particularly, a human) in needthereof. Examples of RIP2 kinase-mediated diseases or disorders includeuveitis, Crohn's disease, ulcerative colitis, early-onset andextraintestinal inflammatory bowel disease and granulomateous disorders,such as sarcoidosis, Blau syndrome, early-onset sarcoidosis and Wegner'sGranulomatosis.

The present invention is further directed to a pharmaceuticalcomposition comprising a compound according to Formula (I), or a salt,particularly a pharmaceutically acceptable salt, thereof and apharmaceutically acceptable excipient. Particularly, this invention isdirected to a pharmaceutical composition for the treatment of a RIP2kinase-mediated disease or disorder, where the composition comprises acompound according to Formula (I), or a salt, particularly apharmaceutically acceptable salt, thereof and a pharmaceuticallyacceptable excipient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a powder x-ray powder diffraction (PXRD) pattern of acrystalline form of calcium (I)2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethylhydrogen phosphate trihydrate.

FIG. 2 is a PXRD pattern of a crystalline form of2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate hydrochloride monohydrate.

FIG. 3 shows the combined cytokine response in rat whole blood samplesobtained after pre-dosing rats with the compound2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethanol,or prednisolone, followed by dosing with L18-MDP.

FIG. 4 shows the blood profile of2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethanolfollowing oral administration of2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate in rat, dog and minipig.

DETAILED DESCRIPTION OF THE INVENTION

The alternative definitions for the various groups and substituentgroups of Formula (I) provided throughout the specification are intendedto particularly describe each compound species disclosed herein,individually, as well as groups of one or more compound species. Thescope of this invention includes any combination of these group andsubstituent group definitions. The compounds of the invention are onlythose which are contemplated to be “chemically stable” as will beappreciated by those skilled in the art.

In addition, it will be appreciated by those skilled in the art that thecompounds of this invention, depending on further substitution, mayexist in other tautomeric forms. All tautomeric forms of the compoundsdescribed herein are intended to be encompassed within the scope of thepresent invention. It is to be understood that any reference to a namedcompound of this invention is intended to encompass all tautomers of thenamed compound and any mixtures of tautomers of the named compound.

As used herein, the term “alkyl” represents a saturated, straight orbranched hydrocarbon moiety. Exemplary alkyls include, but are notlimited to methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl,s-butyl, isobutyl, t-butyl and pentyl. The term “C₁-C₄ alkyl” refers toan alkyl group or moiety containing from 1 to 4 carbon atoms.

“5- or 6-Membered heterocycloalkyl” represents a group or moietycomprising a non-aromatic, monocyclic radical, which is saturated orpartially unsaturated, containing 5 to 6 ring atoms, which includes 1 to4 heteroatoms selected from nitrogen, oxygen and sulfur. Illustrativeexamples of heterocycloalkyls include, but are not limited to,pyrrolidyl (or pyrrolidinyl), piperidinyl, piperazinyl, morpholinyl,tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl (or tetrahydrofuranyl),dihydrofuryl, oxazolinyl, thiazolinyl, pyrazolinyl, tetrahydropyranyl,dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl,1,3-oxathiolanyl, 1,3-oxathianyl, and 1,3-dithianyl.

Heterocycloalkyl groups include 5-membered heterocycloalkyl groupscontaining one heteroatom selected from nitrogen, oxygen and sulfur andoptionally containing one or two additional nitrogen atoms, oroptionally containing one additional oxygen or sulfur atom, such aspyrrolidyl (or pyrrolidinyl), tetrahydrofuryl (or tetrahydrofuranyl),tetrahydrothienyl, dihydrofuryl, oxazolinyl, thiazolinyl, imidazolinyl,pyrazolinyl, 1,3-dioxolanyl, and 1,3-oxathiolan-2-on-yl.

Heterocycloalkyl groups are 6-membered heterocycloalkyl groupscontaining one heteroatom selected from nitrogen, oxygen and sulfur andoptionally containing one or two additional nitrogen atoms or oneadditional oxygen or sulfur atom, such as piperidyl (or piperidinyl),piperazinyl, morpholinyl, thiomorpholinyl,1,1dioxoido-thiomorpholin-4-yl, tetrahydropyranyl, dihydropyranyl,tetrahydro-2H-1,4-thiazinyl, 1,4-dioxanyl, 1,3-oxathianyl, and1,3-dithianyl.

It is to be understood that the term heterocycloalkyl is intended toencompass stable heterocyclic groups where a ring nitrogen heteroatom isoptionally oxidized (e.g., heterocyclic groups containing an N-oxide) orwhere a ring sulfur heteroatom is optionally oxidized (e.g.,heterocyclic groups containing sulfones or sulfoxide moieties, such astetrahydrothienyl-1-oxide (a tetrahydrothienyl sulfoxide) ortetrahydrothienyl-1,1-dioxide (a tetrahydrothienyl sulfone)).

“Oxo” represents a double-bonded oxygen moiety; for example, if attacheddirectly to a carbon atom forms a carbonyl moiety (C═O).

As used herein, the terms “compound(s) of the invention” or “compound(s)of this invention” mean a compound of Formula (I), as defined above, inany form, i.e., any salt or non-salt form (e.g., as a free acid or baseform, or as a salt, particularly a pharmaceutically acceptable saltthereof) and any physical form thereof (e.g., including non-solid forms(e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous orcrystalline forms, specific polymorphic forms, solvate forms, includinghydrate forms (e.g., mono-, di-, tri- and hemi-hydrates)), and mixturesof various forms (various hydrates of a salt form).

As used herein, the term “optionally substituted” indicates that a group(such as an alkyl or heterocycloalkyl group) or ring or moiety may beunsubstituted, or the group, ring or moiety may be substituted with oneor more substituent(s) as defined. In the case where groups may beselected from a number of alternative groups, the selected groups may bethe same or different.

The term “independently” means that where more than one substituent isselected from a number of possible substituents, those substituents maybe the same or different.

In addition, it will be appreciated by those skilled in the art that thecompounds of this invention, depending on further substitution, mayexist in other tautomeric forms. All tautomeric forms of the compoundsdescribed herein are intended to be encompassed within the scope of thepresent invention. It is to be understood that any reference to a namedcompound of this invention is intended to encompass all tautomers of thenamed compound and any mixtures of tautomers of the named compound.

In one embodiment of the compounds of Formula (I) of this invention, Xis

and R^(1a) and R^(1b) are each independently H, (C₁-C₄)alkyl, or—CH₂OCO₂(C₁-C₄)alkyl.

In another embodiment, X is

and R^(1a) and R^(1b) are each independently H or methyl.

In another embodiment, X is

and R⁵ is (C₁-C₆)alkyl substituted by —OH, —OP(═O)(OH)₂, —NH₂, or—NHCO(C₁-C₄)alkyl, wherein the (C₁-C₄)alkyl group of said—NHCO(C₁-C₄)alkyl is optionally substituted by —NH₂.

In another embodiment, X is

and R⁵ is (C₁-C₆)alkyl substituted by —OH or —NH₂.

In another embodiment, X is

and R⁵ is (C₁-C₆)alkyl substituted by —NH₂.

In another embodiment, X is

and R⁵ is —CH(NH₂)(C₁-C₄)alkyl.

In a preferred embodiment, X is

and R^(1a) and R^(1b) are each independently H, or a pharmaceuticallyacceptable salt thereof.

In another preferred embodiment, X is

and R^(1a) and R^(1b) are each independently H, or a pharmaceuticallyacceptable salt thereof, or a hydrate thereof

In another preferred embodiment, X is

and R⁵ is (C₁-C₄)alkyl substituted by —NH₂.

Representative compounds of this invention include:

-   2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl    dihydrogen phosphate,-   (S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl    2-amino-3-methylbutanoate,-   (R)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl    2-amino-3-methylbutanoate, and-   (2S,3S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl    2-amino-3-methylpentanoate,

or a salt thereof

In another embodiment, representative compounds of this inventioninclude the compounds of Examples 1-7, specifically:

-   2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl    dihydrogen phosphate,-   2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl    disodium phosphate,-   calcium (I)    2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl    hydrogen phosphate trihydrate,-   2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl    dihydrogen phosphate hydrochloride monohydrate,-   (S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl    2-amino-3-methylbutanoate, dihydrochloride,-   (R)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl    2-amino-3-methylbutanoate, dihydrochloride, and-   (2S,3S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl    2-amino-3-methylpentanoate.

In another embodiment representative compounds of this inventioninclude:

-   2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl    dihydrogen phosphate,-   2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl    disodium phosphate, and-   (S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl    2-amino-3-methylbutanoate, dihydrochloride.

It will be appreciated that the present invention covers compounds ofFormula (I) as the free base or free acid and as salts thereof, forexample as a pharmaceutically acceptable salt thereof. In one embodimentthe invention relates to compounds of Formula (I) in the form of a freebase or free acid. In another embodiment the invention relates tocompounds of Formula (I) or a pharmaceutically acceptable salt thereof.It will further be appreciated that compounds of Formula (I) and saltsthereof may exist in hydrated from, such as the monohydrate or thetrihydrate.

In one embodiment, the compound of the invention is2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate as the free acid. In another embodiment, thecompound of the invention is2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate or a salt thereof. In another embodiment, thecompound of the invention is2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate or a pharmaceutically acceptable salt thereof. Inanother embodiment, the compound of the invention is2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate or a hydrate thereof. In another embodiment, thecompound of the invention is a pharmaceutically acceptable salt of2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate or a hydrate thereof. In yet another embodiment,the compound of the invention is a sodium, calcium or hydrochloride saltof2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate, or a hydrate thereof.

In a specific embodiment, the compound of the invention is2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldisodium phosphate.

In another specific embodiment, the compound of the invention is calcium(I)2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethylhydrogen phosphate trihydrate. In a further specific embodiment, thecompound of the invention is calcium (I)2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethylhydrogen phosphate trihydrate having the PXRD of FIG. 1.

In yet another specific embodiment, the compound of the invention is2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate hydrochloride monohydrate. In yet a furtherspecific embodiment, the compound of the invention is2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl dihydrogen phosphate hydrochloridemonohydrate having the PXRD of FIG. 2.

In another embodiment the compound of the invention is(S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylbutanoate as the free base. In another embodiment thecompound of the invention is(S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylbutanoate or a salt thereof. In another embodiment thecompound of the invention is(S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylbutanoate or a pharmaceutically acceptable salt thereof.

In another embodiment the compound of the invention is(R)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylbutanoate as the free base. In another embodiment thecompound of the invention is(R)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylbutanoate or a salt thereof. In another embodiment thecompound of the invention is(R)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylbutanoate or a pharmaceutically acceptable salt thereof.

In a further embodiment the compound of the invention is(2S,3S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylpentanoate as the free base. In a further embodiment thecompound of the invention is(2S,3S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylpentanoate or a salt thereof. In a further embodimentthe compound of the invention is(2S,3S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylpentanoate or a pharmaceutically acceptable saltthereof.

Accordingly, a compound of the invention includes a compound of Formula(I), particularly the specific compounds described herein, or a saltthereof, particularly a pharmaceutically acceptable salt thereof.Specifically, a compound of the invention includes a compound of Formula(I), or a pharmaceutically acceptable salt thereof, or a hydratethereof, or a hydrate of a pharmaceutically acceptable salt of acompound of Formula (I) and particularly the specific compoundsdescribed herein. In one embodiment, the invention is directed to amethod of inhibiting RIP2 kinase comprising administering to a host acompound of the invention. In another embodiment, the invention isdirected to a method of treating a RIP2 kinase-mediated disease ordisorder comprising administering a therapeutically effective amount ofa compound of the invention to a human in need thereof.

This invention is directed to a method of treating a disease or disordermediated by inhibition of RIP2 kinase comprising administering atherapeutically effective amount of a compound of the invention to ahuman in need thereof. This invention is particularly directed to amethod of treating a disease or disorder mediated by inhibition of RIP2kinase comprising administering a therapeutically effective amount ofthe compound according to Formula (I) or pharmaceutically acceptablesalt thereof to a human in need thereof.

The invention is still further directed to the use of a compound of theinvention or a pharmaceutical composition comprising a compound of theinvention to inhibit RIP2 kinase and/or treat a RIP2 kinase-mediateddisease or disorder.

The compounds according to Formula (I) may contain one or moreasymmetric center (also referred to as a chiral center) and may,therefore, exist as individual enantiomers, diastereomers, or otherstereoisomeric forms, or as mixtures thereof. Where the stereochemistryof a chiral center present in a compound of this invention (e.g.,compound name) or in any chemical structure illustrated herein is notspecified, the compound, compound name, or structure is intended toencompass all individual stereoisomers and all mixtures thereof. Thus,compounds according to Formula (I) containing one or more chiral centermay be present as racemic mixtures, enantiomerically enriched mixtures,or as enantiomerically pure individual stereoisomers.

Individual stereoisomers of a compound according to Formula (I) whichcontain one or more asymmetric center may be resolved by methods knownto those skilled in the art. For example, such resolution may be carriedout (1) by formation of diastereoisomeric salts, complexes or otherderivatives; (2) by selective reaction with a stereoisomer-specificreagent, for example by enzymatic oxidation or reduction; or (3) bygas-liquid or liquid chromatography in a chiral environment, forexample, on a chiral support such as silica with a bound chiral ligandor in the presence of a chiral solvent. The skilled artisan willappreciate that where the desired stereoisomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step is required to liberate the desired form. Alternatively,specific stereoisomers may be synthesized by asymmetric synthesis usingoptically active reagents, substrates, catalysts or solvents, or byconverting one enantiomer to the other by asymmetric transformation.

It is to be understood that a solid form of a compound of the inventionmay exist in crystalline forms, non-crystalline forms or a mixturethereof. Such crystalline forms may also exhibit polymorphism (i.e. thecapacity to occur in different crystalline forms). These differentcrystalline forms are typically known as “polymorphs.” Polymorphs havethe same chemical composition but differ in packing, geometricalarrangement, and other descriptive properties of the crystalline solidstate. Polymorphs, therefore, may have different physical propertiessuch as shape, density, hardness, deformability, stability, anddissolution properties. Polymorphs typically exhibit different meltingpoints, IR spectra, and X-ray powder diffraction patterns, which may beused for identification. One of ordinary skill in the art willappreciate that different polymorphs may be produced, for example, bychanging or adjusting the conditions used incrystallizing/recrystallizing the compound.

When a compound of the invention is a base (contains a basic moiety), adesired salt form may be prepared by any suitable method known in theart, including treatment of the free base with an inorganic acid, suchas hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like, or with an organic acid, such as aceticacid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, and the like, or with a pyranosidyl acid, such asglucuronic acid or galacturonic acid, or with an alpha-hydroxy acid,such as citric acid or tartaric acid, or with an amino acid, such asaspartic acid or glutamic acid, or with an aromatic acid, such asbenzoic acid or cinnamic acid, or with a sulfonic acid, such asp-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid or thelike.

Suitable addition salts include acetate, p-aminobenzoate, ascorbate,aspartate, benzenesulfonate, benzoate, bicarbonate,bismethylenesalicylate, bisulfate, bitartrate, borate, calcium edetate,camsylate, carbonate, clavulanate, citrate, cyclohexylsulfamate,edetate, edisylate, estolate, esylate, ethanedisulfonate,ethanesulfonate, formate, fumarate, gluceptate, gluconate, glutamate,glycollate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, dihydrochloride, hydrofumarate, hydrogenphosphate, hydroiodide, hydromaleate, hydrosuccinate, hydroxynaphthoate,isethionate, itaconate, lactate, lactobionate, laurate, malate, maleate,mandelate, mesylate, methylsulfate, monopotassium maleate, mucate,napsylate, nitrate, N-methylglucamine, oxalate, oxaloacetate, pamoate(embonate), palmate, palmitate, pantothenate, phosphate/diphosphate,pyruvate, polygalacturonate, propionate, saccharate, salicylate,stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate,tosylate, triethiodide, trifluoroacetate and valerate.

Other exemplary acid addition salts include pyrosulfate, sulfite,bisulfate, decanoate, caprylate, acrylate, isobutyrate, caproate,heptanoate, propiolate, oxalate, malonate, sub erate, sebacate,butyne-1,4-dioate, hexyne-1,6-dioate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,phenylacetate, phenylpropionate, phenylbutrate, lactate,γ-hydroxybutyrate, mandelate, and sulfonates, such as xylenesulfonate,propanesulfonate, naphthalene-1-sulfonate and naphthalene-2-sulfonate.

If an inventive basic compound is isolated as a salt, the correspondingfree base form of that compound may be prepared by any suitable methodknown to the art, including treatment of the salt with an inorganic ororganic base, suitably an inorganic or organic base having a higherpK_(a) than the free base form of the compound.

When a compound of the invention is an acid (contains an acidic moiety),a desired salt may be prepared by any suitable method known to the art,including treatment of the free acid with an inorganic or organic base,such as an amine (primary, secondary, or tertiary), an alkali metal oralkaline earth metal hydroxide, or the like. Illustrative examples ofsuitable salts include organic salts derived from amino acids such asglycine and arginine, ammonia, primary, secondary, and tertiary amines,and cyclic amines, such as N-methyl-D-glucamine, diethylamine,isopropylamine, trimethylamine, ethylene diamine, dicyclohexylamine,ethanolamine, piperidine, morpholine, and piperazine, as well asinorganic salts derived from sodium, calcium, potassium, magnesium,manganese, iron, copper, zinc, aluminum, and lithium.

Because of their potential use in medicine, the salts of the compoundsof Formula (I) are preferably pharmaceutically acceptable salts.Suitable pharmaceutically acceptable salts include acid or base additionsalts, such as those described by Berge, Bighley and Monkhouse J. Pharm.Sci (1977) 66, pp 1-19 and “Pharmaceutical Salts: Properties, Selection,and Use, 2nd Revised Edition,” P. H. Stahl and C. G. Wermuth (eds.),Wiley, Hoboken, N.J., US (2011). The term “pharmaceutically acceptable”refers to those compounds, materials, compositions, and dosage formswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of human beings and animals withoutexcessive toxicity, irritation, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

“Pharmaceutically acceptable salt(s)” refers to a compound which issuitable for pharmaceutical use. Salt and solvate (e.g. hydrates andhydrates of salts) forms of the compounds of Formula (I) which aresuitable for use in medicine are those wherein the counterion orassociated solvent is pharmaceutically acceptable. However, salts andsolvates having non-pharmaceutically acceptable counterions orassociated solvents are within the scope of the present invention, forexample, for use as intermediates in the preparation of other compoundsof the invention and their salts and solvates.

Examples of pharmaceutically acceptable acid-addition salts includeacetate, adipate, ascorbate, aspartate, benzenesulfonate, benzoate,camphorate, camphor-sulfonate (camsylate), caprate (decanoate), caproate(hexanoate), caprylate (octanoate), carbonate, bicarbonate, cinnamate,citrate, cyclamate, dodecylsulfate (estolate), ethane-1,2-disulfonate(edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate(mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate(gluceptate), gluconate, glucuronate, glutamate, glutarate,glycerophosphorate, glycolate, hippurate, hydrobromide, hydrochloride,hydroiodide, isobutyrate, lactate, lactobionate, laurate, maleate,malate, malonate, mandelate, methanesulfonate (mesylate),naphthalene-1,5-disulfonate (napadisylate), naphthalene-sulfonate(napsylate), nicotinate, nitrate, oleate, oxalate, palmitate, pamoate,phosphate, diphosphate, proprionate, pyroglutamate, salicylate,sebacate, stearate, succinate, sulfate, tartrate, thiocyanate, tosylate,undecylenate, 1-hydroxy-2-naphthoate, 2,2-dichloroacetate,2-hydroxyethanesulfonate (isethionate), 2-oxoglutarate,4-acetamidobenzoate, and 4-aminosalicylate. In one embodiment thepharmaceutically acceptable acid addition salt is hydrochloride (e.g., amonohydrochloride or dihydrochloride salt). Non-pharmaceuticallyacceptable salts, e.g. trifluoroacetate, may be used, for example in theisolation of a compound of Formula (I), and are included within thescope of this invention.

Examples of pharmaceutically acceptable base-addition salts includeammonium, lithium, sodium, potassium, calcium, magnesium, aluminumsalts, zinc salts, trimethylamine, triethylamine, morpholine, pyridine,piperidine, picoline, dicyclohexylamine, N,N′-dibenzylethylenediamine,2-hydroxyethylamine, bis-(2-hydroxyethyl)amine,tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine,dehydroabietylamine, glucamine, N-methylglucamine, collidine, quinine,quinoline, lysine and arginine. In one embodiment the pharmaceuticallyacceptable base-addition salt is sodium or calcium. In anotherembodiment the pharmaceutically acceptable base-addition salt is sodium.In another embodiment the pharmaceutically acceptable base-addition saltis calcium.

Certain of the compounds of the invention may form salts with one ormore equivalents of an acid (if the compound contains a basic moiety) ora base (if the compound contains an acidic moiety). The presentinvention includes within its scope all possible stoichiometric andnon-stoichiometric salt forms.

Compounds of the invention having both a basic and acidic moiety may bein the form of zwitterions, acid-addition salt of the basic moiety orbase salts of the acidic moiety.

This invention also provides for the conversion of one pharmaceuticallyacceptable salt of a compound of this invention into anotherpharmaceutically acceptable salt of a compound of this invention.

If an inventive basic compound is isolated as a salt, the correspondingfree acid or free base form of that compound may be prepared by anysuitable method known to the art.

For solvates of the compounds of Formula (I), including solvates ofsalts of the compounds of Formula (I), that are in crystalline form, theskilled artisan will appreciate that pharmaceutically acceptablesolvates may be formed wherein solvent molecules are incorporated intothe crystalline lattice during crystallization. Solvates may involvenonaqueous solvents such as ethanol, isopropanol, DMSO, acetic acid,ethanolamine, and EtOAc, or they may involve water as the solvent thatis incorporated into the crystalline lattice. Solvates wherein water isthe solvent that is incorporated into the crystalline lattice aretypically referred to as “hydrates.” Hydrates include stoichiometrichydrates as well as compositions containing variable amounts of water.The invention includes all such solvates, particularly hydrates, forexample the monohydrate or trihydrate. Accordingly, a compound of thisinvention includes a compound of Formula (I), or a salt thereof,particularly a pharmaceutically acceptable salt thereof, or a hydratethereof, a hydrate of a pharmaceutically acceptable salt of a compoundof Formula (I) and particularly includes each compound described in theExamples. Thus the invention provides a compound of Formula (I) or asalt thereof, especially a pharmaceutically acceptable salt thereof, asa solvate, particularly as a hydrate, such as a monohydrate ortrihydrate.

Because the compounds of Formula (I) are intended for use inpharmaceutical compositions it will readily be understood that they areeach preferably provided in substantially pure form, for example atleast 60% pure, more suitably at least 75% pure and preferably at least85%, especially at least 98% pure (% are on a weight for weight basis).Impure preparations of the compounds may be used for preparing the morepure forms used in the pharmaceutical compositions.

The compounds of the invention may be particularly useful for treatmentof RIP2 kinase-mediated diseases or disorders, particularly diseases ordisorders mediated by inhibition of RIP2 kinase, such as uveitis,interleukin-1 converting enzyme (ICE, also known as Caspase-1)associated fever syndrome (ICE fever), dermatitis, acute lung injury,type 2 diabetes mellitus, arthritis (specifically rheumatoid arthritis),inflammatory bowel disorders (such as ulcerative colitis and Crohn'sdisease), early-onset inflammatory bowel disease, extraintestinalinflammatory bowel disease, prevention of ischemia reperfusion injury insolid organs (specifically kidney) in response ischemia induced bycardiac surgery, organ transplant, sepsis and other insults, liverdiseases (non-alcohol steatohepatitis, alcohol steatohepatitis, andautoimmune hepatitis), allergic diseases (such as asthma), transplantreactions (such as graft versus host disease), autoimmune diseases (suchas systemic lupus erythematosus, and multiple sclerosis), andgranulomateous disorders (such as sarcoidosis, Blau syndrome,early-onset sarcoidosis, Wegner's granulomatosis, and interstitialpulmonary disease).

The compounds of this invention may be particularly useful in thetreatment of uveitis, ICE fever, Blau Syndrome, early-onset sarcoidosis,ulcerative colitis, Crohn's disease, Wegener's granulamatosis andsarcoidosis.

In one embodiment the invention is directed to a method of treatinguveitis comprising administering a therapeutically effective amount ofthe compound according to Formula (I) or a pharmaceutically acceptablesalt thereof, to a human in need thereof. In another embodiment theinvention is directed to a method of treating interleukin-1 convertingenzyme associated fever syndrome comprising administering atherapeutically effective amount of the compound according to Formula(I) or a pharmaceutically acceptable salt thereof, to a human in needthereof. In another embodiment the invention is directed to a method oftreating Blau syndrome comprising administering a therapeuticallyeffective amount of the compound according to Formula (I) or apharmaceutically acceptable salt thereof, to a human in need thereof. Inanother embodiment the invention is directed to a method of treatingearly-onset sarcoidosis comprising administering a therapeuticallyeffective amount of the compound according to Formula (I) or apharmaceutically acceptable salt thereof, to a human in need thereof. Inanother embodiment the invention is directed to a method of treatingulcerative colitis comprising administering a therapeutically effectiveamount of the compound according to Formula (I) or a pharmaceuticallyacceptable salt thereof, to a human in need thereof. In anotherembodiment the invention is directed to a method of treating Crohn'sdisease comprising administering a therapeutically effective amount ofthe compound according to Formula (I) or a pharmaceutically acceptablesalt thereof, to a human in need thereof. In another embodiment theinvention is directed to a method of treating Wegner's Granulomatosiscomprising administering a therapeutically effective amount of thecompound according to Formula (I) or a pharmaceutically acceptable saltthereof, to a human in need thereof. In a further embodiment theinvention is directed to a method of treating sarcoidosis comprisingadministering a therapeutically effective amount of the compoundaccording to Formula (I) or a pharmaceutically acceptable salt thereof,to a human in need thereof.

Treatment of RIP2 kinase-mediated diseases or disorders, or morebroadly, treatment of immune mediated diseases including, but notlimited to, allergic diseases, autoimmune diseases, prevention oftransplant rejection and the like, may be achieved using a compound ofthis invention as a monotherapy, or in dual or multiple combinationtherapy, particularly for the treatment of refractory cases, such as incombination with other anti-inflammatory and/or anti-TNF agents, whichmay be administered in therapeutically effective amounts as is known inthe art.

The compounds of Formula (I) and pharmaceutically acceptable saltsthereof may be employed alone or in combination with other therapeuticagents. Combination therapies according to the present invention thuscomprise the administration of at least one compound of Formula (I) or apharmaceutically acceptable salt thereof, and the use of at least oneother therapeutically active agent. Preferably, combination therapiesaccording to the present invention comprise the administration of atleast one compound of Formula (I) or a pharmaceutically acceptable saltthereof, and at least one other therapeutically active agent. Thecompound(s) of Formula (I) and pharmaceutically acceptable saltsthereof, and the other therapeutically active agent(s) may beadministered together in a single pharmaceutical composition orseparately and, when administered separately this may occursimultaneously or sequentially in any order. The amounts of thecompound(s) of Formula (I) and pharmaceutically acceptable saltsthereof, and the other therapeutically active agent(s) and the relativetimings of administration will be selected in order to achieve thedesired combined therapeutic effect. Thus in a further aspect, there isprovided a combination comprising a compound of Formula (I) or apharmaceutically acceptable salt thereof, together with one or moreother therapeutically active agents.

Thus in one aspect, the compound of Formula (I) or a pharmaceuticallyacceptable salt thereof, and pharmaceutical compositions comprising acompound of formula (I) or a pharmaceutically acceptable salt thereof,according to the invention may be used in combination with or includeone or more other therapeutic agents, for example an anti-inflammatoryagent and/or an anti-TNF agent.

The compounds of this invention may be administered in combination withcorticosteroids and/or anti-TNF agents to treat Blau syndrome,early-onset sarcoidosis; or in combination with anti-TNF biologics orother anti-inflammatory biologics to treat Crohn's Disease; or incombination with 5-ASA (mesalamine) or sulfasalazine to treat ulcerativecolitis; or in combination with low-dose corticosteroids and/ormethotrexate to treat Wegener's granulamatosis or sarcoidosis orinterstitial pulmonary disease; or in combination with a biologic (e.g.anti-TNF, anti-IL-6, etc.) to treat rheumatoid arthritis; or incombination with anti-IL6 and/or methotrexate to treat ICE fever.

Examples of suitable anti-inflammatory agents include 5-aminosalicyclicacid and mesalamine preparations, sulfasalazine, hydroxycloroquine,thiopurines (azathioprin, mercaptopurin), methotrexate,cyclophosphamide, cyclosporine, JAK inhibitors (tofacitinib),corticosteroids, particularly low-dose corticosteroids (such asprednisone (Deltasone®) and bundesonide) and anti-inflammatory biologicssuch as anti-IL6R mAbs (Actemra® (tocilizumab)), anti-IL6 biologics,anti-IL1 or IL12 or IL23 biologics (ustekinumab (Stelara®)),anti-integrin agents (natalizumab (Tysabri®)), anti-CD20 mAbs (rituximab(Rituxan®) and ofatumumab (Arzerra®)), and other agents, such asabatacept (Orencia®), anakinra (Kineret®), and belimumab (Benlysta®),CD4 biologics and other cytokine inhibitors or biologics to T-cell orB-cell receptors or interleukins. Examples of suitable anti-TNF agentsinclude the anti-TNF biologics such as Enbrel® (etanecerpt), Humira®(adalimumab), Remicade® (infliximab), Cimzia® (certolizumab), andSimponi® (golimumab).

This invention provides a compound of the invention for use in therapy.This invention also provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in therapy.Specifically, this invention provides the compounds described herein foruse in therapy.

In another embodiment, this invention provides a compound of theinvention for use in the treatment of a disease or disorder mediated byinhibition of RIP2 kinase. In another embodiment, this inventionprovides a compound of Formula (I), or a pharmaceutically acceptablesalt thereof, for use in the treatment of a disease or disorder mediatedby inhibition of RIP2 kinase. Specifically, this invention provides thecompounds described herein for use in the treatment of a disease ordisorder mediated by inhibition of RIP2 kinase. In another embodimentthis invention provides a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, for use in the treatment of uveitis,interleukin-1 converting enzyme associated fever syndrome, dermatitis,acute lung injury, type 2 diabetes mellitus, arthritis, rheumatoidarthritis, ulcerative colitis, Crohn's disease, early-onset inflammatorybowel disease, extraintestinal inflammatory bowel disease, prevention ofischemia reperfusion injury in solid organ transplant, non-alcoholsteatohepatitis, alcohol steatohepatitis, autoimmune hepatitis, asthma,graft versus host disease, systemic lupus erythematosus, multiplesclerosis, sarcoidosis, Blau syndrome/early-onset sarcoidosis, Wegner'sgranulomatosis or interstitial pulmonary disease. In another embodimentthis invention provides a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, for use in the treatment of uveitis. In anotherembodiment this invention provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofinterleukin-1 converting enzyme associated fever syndrome. In anotherembodiment this invention provides a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofBlau syndrome. In another embodiment this invention provides a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, for usein the treatment of early-onset sarcoidosis. In another embodiment thisinvention provides a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, for use in the treatment of ulcerative colitis.In another embodiment this invention provides a compound of Formula (I),or a pharmaceutically acceptable salt thereof, for use in the treatmentof Crohn's disease. In another embodiment this invention provides acompound of Formula (I), or a pharmaceutically acceptable salt thereof,for use in the treatment of early-onset inflammatory bowel disease. Inanother embodiment this invention provides a compound of Formula (I), ora pharmaceutically acceptable salt thereof, for use in the treatment ofextraintestinal inflammatory bowel disease. In another embodiment thisinvention provides a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, for use in the treatment of Wegner'sGranulomatosis. In another embodiment this invention provides a compoundof Formula (I), or a pharmaceutically acceptable salt thereof, for usein the treatment of sarcoidosis.

This invention specifically provides for the use of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, as an activetherapeutic substance in the treatment of a RIP2 kinase-mediated diseaseor disorder, for example the diseases and disorders recited herein. Morespecifically, this invention provides for the use of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, for thetreatment of a disease or disorder mediated by inhibition of RIP2kinase. This invention specifically provides for the use of thecompounds described herein for the treatment of a disease or disordermediated by inhibition of RIP2 kinase. Accordingly, the inventionprovides for the use of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, as an active therapeutic substance in thetreatment of a human in need thereof with a disease mediated byinhibition of RIP2 kinase.

The invention also provides for the use of a compound of Formula (I), ora pharmaceutically acceptable salt thereof, in the manufacture of amedicament for use in the treatment of a RIP2 kinase-mediated disease ordisorder, for example the diseases and disorders recited herein. Morespecifically, this invention provides for the use of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment of a disease or disordermediated by inhibition of RIP2 kinase. Accordingly, the inventionprovides for the use of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for use inthe treatment of a human in need thereof with a disease or disordermediated by inhibition of

RIP2 kinase. In one embodiment this invention provides for the use of acompound of Formula (I), or a pharmaceutically acceptable salt thereof,in the manufacture of a medicament for use in the treatment of uveitis,interleukin-1 converting enzyme associated fever syndrome, dermatitis,acute lung injury, type 2 diabetes mellitus, arthritis, rheumatoidarthritis, ulcerative colitis, Crohn's disease, early-onset inflammatorybowel disease, extraintestinal inflammatory bowel disease, prevention ofischemia reperfusion injury in solid organ transplant, non-alcoholsteatohepatitis, alcohol steatohepatitis, autoimmune hepatitis, asthma,graft versus host disease, systemic lupus erythematosus, multiplesclerosis, sarcoidosis, Blau syndrome/early-onset sarcoidosis, Wegner'sgranulomatosis or interstitial pulmonary disease. In another embodimentthis invention provides for the use of a compound of Formula (I), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for use in the treatment of uveitis. In another embodimentthis invention provides for the use of a compound of Formula (I), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for use in the treatment of interleukin-1 converting enzymeassociated fever syndrome. In another embodiment this invention providesfor the use of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for use inthe treatment of early-onset sarcoidosis. In another embodiment thisinvention provides for the use of a compound of Formula (I), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for use in the treatment of ulcerative colitis. In anotherembodiment this invention provides for the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, in the manufactureof a medicament for use in the treatment of Crohn's disease. In anotherembodiment this invention provides for the use of a compound of Formula(I), or a pharmaceutically acceptable salt thereof, in the manufactureof a medicament for use in the treatment of Wegner's Granulomatosis. Inanother embodiment this invention provides for the use of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of sarcoidosis. Inanother embodiment this invention provides for the use of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of early-onsetinflammatory bowel disease. In another embodiment this inventionprovides for the use of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, in the manufacture of a medicament for use inthe treatment of extraintestinal inflammatory bowel disease. In afurther embodiment this invention provides for the use of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for use in the treatment of Blau syndrome.

A therapeutically “effective amount” is intended to mean that amount ofa compound that, when administered to a patient in need of suchtreatment, is sufficient to effect treatment, as defined herein. Thus,e.g., a therapeutically effective amount of a compound of Formula (I),or a pharmaceutically acceptable salt thereof, or hydrate thereof, is aquantity of an inventive agent that, when administered to a human inneed thereof, is sufficient to modulate or inhibit the activity of RIP2kinase such that a disease condition which is mediated by that activityis reduced, alleviated or prevented. The amount of a given compound thatwill correspond to such an amount will vary depending upon factors suchas the particular compound (e.g., the potency (pIC₅₀), efficacy (EC₅₀),and the biological half-life of the particular compound), diseasecondition and its severity, the identity (e.g., age, size and weight) ofthe patient in need of treatment, but can nevertheless be routinelydetermined by one skilled in the art. Likewise, the duration oftreatment and the time period of administration (time period betweendosages and the timing of the dosages, e.g., before/with/after meals) ofthe compound will vary according to the identity of the mammal in needof treatment (e.g., weight), the particular compound and its properties(e.g., pharmaceutical characteristics), disease or disorder and itsseverity and the specific composition and method being used, but cannevertheless be determined by one of skill in the art.

“Treating” or “treatment” is intended to mean at least the mitigation ofa disease or disorder in a patient. The methods of treatment formitigation of a disease or disorder include the use of the compounds inthis invention in any conventionally acceptable manner, for example forprevention, retardation, prophylaxis, therapy or cure of a mediateddisease or disorder. Specific diseases and disorders that may beparticularly susceptible to treatment using a compound of this inventionare described herein.

The compounds of the invention may be administered by any suitable routeof administration, including both systemic administration and topicaladministration. Systemic administration includes oral administration,parenteral administration, transdermal administration, rectaladministration, and administration by inhalation. Parenteraladministration refers to routes of administration other than enteral,transdermal, or by inhalation, and is typically by injection orinfusion. Parenteral administration includes intravenous, intramuscular,and subcutaneous injection or infusion. Inhalation refers toadministration into the patient's lungs whether inhaled through themouth or through the nasal passages. Topical administration includesapplication to the skin.

The compounds of the invention may be administered once or according toa dosing regimen wherein a number of doses are administered at varyingintervals of time for a given period of time. For example, doses may beadministered one, two, three, or four times per day. Doses may beadministered until the desired therapeutic effect is achieved orindefinitely to maintain the desired therapeutic effect. Suitable dosingregimens for a compound of the invention depend on the pharmacokineticproperties of that compound, such as absorption, distribution, andhalf-life, which can be determined by the skilled artisan. In addition,suitable dosing regimens, including the duration such regimens areadministered, for a compound of the invention depend on the disease ordisorder being treated, the severity of the disease or disorder beingtreated, the age and physical condition of the patient being treated,the medical history of the patient to be treated, the nature ofconcurrent therapy, the desired therapeutic effect, and like factorswithin the knowledge and expertise of the skilled artisan. It will befurther understood by such skilled artisans that suitable dosingregimens may require adjustment given an individual patient's responseto the dosing regimen or over time as individual patient needs change.

For use in therapy, the compounds of the invention will be normally, butnot necessarily, formulated into a pharmaceutical composition prior toadministration to a patient. Accordingly, the invention also is directedto pharmaceutical compositions comprising a compound of the inventionand one or more pharmaceutically acceptable excipients.

In one embodiment there is provided a pharmaceutical compositioncomprising2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate as the free acid and one or more pharmaceuticallyacceptable excipients. In another embodiment, there is provided apharmaceutical composition comprising2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate or a pharmaceutically acceptable salt thereof andone or more pharmaceutically acceptable excipients. In anotherembodiment, there is provided a pharmaceutical composition comprising2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate or a hydrate thereof and one or morepharmaceutically acceptable excipients. In another embodiment, there isprovided a pharmaceutical composition comprising a pharmaceuticallyacceptable salt of2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate or a hydrate thereof and one or morepharmaceutically acceptable excipients. In yet another embodiment, thereis provided a pharmaceutical composition comprising a sodium, calcium orhydrochloride salt of2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate, or a hydrate thereof and one or morepharmaceutically acceptable excipients.

In a specific embodiment, there is provided a pharmaceutical compositioncomprising2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldisodium phosphate and one or more pharmaceutically acceptableexcipients.

In another specific embodiment, there is provided a pharmaceuticalcomposition comprising calcium (I)2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethylhydrogen phosphate trihydrate and one or more pharmaceuticallyacceptable excipients. In a further specific embodiment, there isprovided a pharmaceutical composition comprising calcium (I)2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethylhydrogen phosphate trihydrate having the PXRD of FIG. 1 and one or morepharmaceutically acceptable excipients.

In yet another specific embodiment, there is provided a pharmaceuticalcomposition comprising2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate hydrochloride monohydrate and one or morepharmaceutically acceptable excipients. In yet a further specificembodiment, there is provided a pharmaceutical composition comprising2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate hydrochloride monohydrate having the PXRD of FIG. 2and one or more pharmaceutically acceptable excipients.

In another embodiment there is provided a pharmaceutical compositioncomprising(S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylbutanoate as the free base and one or morepharmaceutically acceptable excipients. In another embodiment there isprovided a pharmaceutical composition comprising(S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylbutanoate or a pharmaceutically acceptable salt thereofand one or more pharmaceutically acceptable excipients.

In another embodiment there is provided a pharmaceutical compositioncomprising(R)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylbutanoate as the free base and one or morepharmaceutically acceptable excipients. In another embodiment there isprovided a pharmaceutical composition comprising(R)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylbutanoate or a pharmaceutically acceptable salt thereofand one or more pharmaceutically acceptable excipients.

In a further embodiment there is provided a pharmaceutical compositioncomprising(2S,3S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylpentanoate as the free base and one or morepharmaceutically acceptable excipients. In a further embodiment there isprovided a pharmaceutical composition comprising(2S,3S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylpentanoate or a pharmaceutically acceptable salt thereofand one or more pharmaceutically acceptable excipients.

The pharmaceutical compositions of the invention may be prepared andpackaged in bulk form wherein an effective amount of a compound of theinvention can be extracted and then given to the patient such as withpowders, syrups, and solutions for injection. Alternatively, thepharmaceutical compositions of the invention may be prepared andpackaged in unit dosage form. For oral application, for example, one ormore tablets or capsules may be administered. A dose of thepharmaceutical composition contains at least a therapeutically effectiveamount of a compound of this invention (i.e., a compound of Formula (I),or a salt, particularly a pharmaceutically acceptable salt, thereof).When prepared in unit dosage form, the pharmaceutical compositions maycontain from 1 mg to 1000 mg of a compound of this invention.

As provided herein, unit dosage forms (pharmaceutical compositions)containing from 1 mg to 1000 mg of a compound of the invention may beadministered one, two, three, or four times per day, preferably one,two, or three times per day, and more preferably, one or two times perday, to effect treatment of a RIP2 mediated disease or disorder. Thepharmaceutical compositions of the invention typically contain onecompound of the invention. However, in certain embodiments, thepharmaceutical compositions of the invention contain more than onecompound of the invention. In addition, the pharmaceutical compositionsof the invention may optionally further comprise one or more additionalpharmaceutically active compounds.

As used herein, “pharmaceutically acceptable excipient” means amaterial, composition or vehicle involved in giving form or consistencyto the composition. Each excipient must be compatible with the otheringredients of the pharmaceutical composition when commingled such thatinteractions which would substantially reduce the efficacy of thecompound of the invention when administered to a patient andinteractions which would result in pharmaceutical compositions that arenot pharmaceutically acceptable are avoided. In addition, each excipientmust of course be of sufficiently high purity to render itpharmaceutically acceptable.

The compounds of the invention and the pharmaceutically acceptableexcipient or excipients will typically be formulated into a dosage formadapted for administration to the patient by the desired route ofadministration. Conventional dosage forms include those adapted for (1)oral administration such as tablets, capsules, caplets, pills, troches,powders, syrups, elixirs, suspensions, solutions, emulsions, sachets,and cachets; (2) parenteral administration such as sterile solutions,suspensions, and powders for reconstitution; (3) transdermaladministration such as transdermal patches; (4) rectal administrationsuch as suppositories; (5) inhalation such as aerosols and solutions;and (6) topical administration such as creams, ointments, lotions,solutions, pastes, sprays, foams, and gels.

Suitable pharmaceutically acceptable excipients will vary depending uponthe particular dosage form chosen. In addition, suitablepharmaceutically acceptable excipients may be chosen for a particularfunction that they may serve in the composition. For example, certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of uniform dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of stable dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the carrying or transporting the compound or compounds ofthe invention once administered to the patient from one organ, orportion of the body, to another organ, or portion of the body. Certainpharmaceutically acceptable excipients may be chosen for their abilityto enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the followingtypes of excipients: diluents, fillers, binders, disintegrants,lubricants, glidants, granulating agents, coating agents, wettingagents, solvents, co-solvents, suspending agents, emulsifiers,sweeteners, flavoring agents, flavor masking agents, coloring agents,anti-caking agents, humectants, chelating agents, plasticizers,viscosity increasing agents, antioxidants, preservatives, stabilizers,surfactants, and buffering agents. The skilled artisan will appreciatethat certain pharmaceutically acceptable excipients may serve more thanone function and may serve alternative functions depending on how muchof the excipient is present in the formulation and what otheringredients are present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enablethem to select suitable pharmaceutically acceptable excipients inappropriate amounts for use in the invention. In addition, there are anumber of resources that are available to the skilled artisan whichdescribe pharmaceutically acceptable excipients and may be useful inselecting suitable pharmaceutically acceptable excipients. Examplesinclude Remington's Pharmaceutical Sciences (Mack Publishing Company),The Handbook of Pharmaceutical Additives (Gower Publishing Limited), andThe Handbook of Pharmaceutical Excipients (the American PharmaceuticalAssociation and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared usingtechniques and methods known to those skilled in the art. Some of themethods commonly used in the art are described in Remington'sPharmaceutical Sciences (Mack Publishing Company).

In one aspect, the invention is directed to a solid oral dosage formsuch as a tablet or capsule comprising an effective amount of a compoundof the invention and a diluent or filler. Suitable diluents and fillersinclude lactose, sucrose, dextrose, mannitol, sorbitol, starch (e.g.corn starch, potato starch, and pre-gelatinized starch), cellulose andits derivatives (e.g. microcrystalline cellulose), calcium sulfate, anddibasic calcium phosphate. The oral solid dosage form may furthercomprise a binder. Suitable binders include starch (e.g. corn starch,potato starch, and pre-gelatinized starch), gelatin, acacia, sodiumalginate, alginic acid, tragacanth, guar gum, povidone, and celluloseand its derivatives (e.g. microcrystalline cellulose). The oral soliddosage form may further comprise a disintegrant. Suitable disintegrantsinclude crospovidone, sodium starch glycolate, croscarmelose, alginicacid, and sodium carboxymethyl cellulose. The oral solid dosage form mayfurther comprise a lubricant. Suitable lubricants include stearic acid,magnesium stearate, calcium stearate, and talc.

EXAMPLES

The following examples illustrate the invention. These examples are notintended to limit the scope of the present invention, but rather toprovide guidance to the skilled artisan to prepare and use thecompounds, compositions, and methods of the present invention. Whileparticular embodiments of the present invention are described, theskilled artisan will appreciate that various changes and modificationscan be made without departing from the spirit and scope of theinvention.

Names for the intermediate and final compounds described herein weregenerated using the software naming program ACD/Name Pro V6.02 availablefrom Advanced Chemistry Development, Inc., 110 Yonge Street, 14^(th)Floor, Toronto, Ontario, Canada, M5C 1T4 (http://www.acdlabs.com/) orthe naming program in ChemDraw, Struct=Name Pro 12.0, as part ofChemBioDraw Ultra, available from CambridgeSoft. 100 CambridgeParkDrive, Cambridge, Mass. 02140 USA (www.cambridgesoft.com). It will beappreciated by those skilled in the art that in certain instances thisprogram will name a structurally depicted compound as a tautomer of thatcompound. It is to be understood that any reference to a named compoundor a structurally depicted compound is intended to encompass alltautomers of such compounds and any mixtures of tautomers thereof.

In the following experimental descriptions, the following abbreviationsmay be used:

Abbreviation Meaning AcOH acetic acid aq aqueous brine saturated aqueoussodium chloride CH₂Cl₂ or DCM methylene chloride CH₃CN or MeCNacetonitrile CH₃NH₂ methylamine d day DCE 1,2-dichloroethane DMAP4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethylsulfoxideEDC 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide equiv equivalents Etethyl Et₃N or TEA triethylamine Et₂O diethyl ether EtOAc ethyl acetateh, hr(s) hour(s) HATU O-(7-Azabenzotriazol-1yl)-N,N,N′,N′-tetramethylyronium hexafluorophosphate HCl hydrochloric acid ICl iodinemonochloride i-Pr₂NEt N′,N′-diisopropylethylamine KOt-Bu potassiumtert-butoxide LCMS liquid chromatography-mass spectroscopy LiHDMSlithium•hexamethyldisilazide Me methyl MeOH or CH₃OH methanol MgSO₄magnesium sulfate min minute(s) MS mass spectrum μw microwave Na₂CO₃sodium carbonate NaHCO₃ sodium bicarbonate NaOH sodium hydroxide Na₂SO₄sodium sulfate N₂H₂ hydrazine NH₄Cl ammonium chloride NiCl₂•6H₂O nickel(II) chloride hexahydrate NMP N-methyl-2-pyrrolidone Ph phenyl POCl₃phosphoryl chloride rt room temperature satd. saturated SPE solid phaseextraction TFA trifluoroacetic acid THF tetrahydrofuran t_(R) retentiontime

Preparation 1N-(6-(tert-Butylthio)-7-methoxyquinazolin-4-yl)benzo[d]thiazol-5-amine

Step 1. Methyl 2-amino-4-methoxybenzoate: To a solution of2-amino-4-(methyloxy) benzoic acid (5 g, 30 mmol) in MeOH (30 mL) andtoluene (60 mL) was added trimethylsilyldiazomethane (30 mL, 60 mmol).The reaction mixture was stirred at 0° C. for 1 h. The reaction mixturewas allowed to warm to rt and solvent was removed in vacuo. The crudematerial was purified by column chromatography (0 to 15% EtOAc/hexanes)to provide 4.2 g of the title compound (74%). MS: m/z: 182 [M+H]⁺.

Step 2. Methyl 2-amino-5-iodo-4-methoxybenzoate: Methyl2-amino-4-(methyloxy) benzoate (3.78 g, 20.86 mmol) was dissolved in 25mL of water, 15 mL of ethanol and 2.2 mL of concentrated HCl. A solutionof IC1 (1.1 mL, 21.9 mmol) in 3.8 mL concentrated HCl and 14 mL of waterat 5° C. was added to the aniline solution. The reaction was stirredovernight and was then filtered to obtain 6.9 g of a light brown solid.MS: m/z: 308 [M+H]⁺

Step 3. 6-iodo-7-methoxyquinazolin-4(1H)-one: A solution of methyl2-amino-5-iodo-4-(methyloxy)benzoate (2 g, 6.5 mmol) and imidoformamide(2.0 g, 19.5 mmol) in 2-methoxyethanol (15 mL) was stirred at 125° C.for 6 h. The solvent was removed in vacuo, and the residue was suspendedin water and the solid was collected by filtration, washed with waterand dried under vacuum (50° C.) to afford 2.1 g of the title compound(96% pure). MS: m/z: 303 [M+H]⁺.

Step 4. 4-chloro-6-iodo-7-(methyloxy)quinazoline:6-Iodo-7-(methyloxy)-4(1H)-quinazolinone (2.0 g, 6.6 mmol), POCl₃(3.1mL, 33.1 mmol) and DIPEA (6.9 mL, 40 mmol) were combined in DCE (50 mL)in a round bottom flask. The reaction mixture was heated at 80° C. for 5h, followed by heating at 70° C. overnight. The reaction mixture wasallowed to cool to rt. A yellow solid was precipitated out. The solidwas filtered. The solution was concentrated and neutralized with satd.NaHCO₃, extracted with CH₂Cl₂ and dried over Na₂SO₄. The mixture wasfiltered, and the solvent was removed in vacuo. Solid portions werecombined to obtain 2.0 g of the title compound (88%, 93% pure)). MS:m/z: 321 [M+H]⁺.

Step 5. N-1,3-benzothiazol-5-yl-6-iodo-7-(methyloxy)-4-quinazolinamine:To a solution of 4-chloro-6-iodo-7-(methyloxy)quinazoline (2.0 g, 5.4mmol) in 1-propanol (30 mL) was added 1,3-benzothiazol-5-amine (1.2 g,8.1 mmol). The suspension was heated in oil bath at 90° C. (preheated).The reaction mixture was stirred at this temperature for 30 min. Ayellow solid precipitated out as the reaction mixture was allowed tocool to rt. The solid was filtered, washed with toluene and dried toprovide 1.3 g of the title compound (55.2%, 99% pure). MS: m/z: 435[M+H]⁺.

Step 6.N-(6-(tert-butylthio)-7-methoxyquinazolin-4-yl)benzo[d]thiazol-5-amine:To a solution ofN-1,3-benzothiazol-5-yl-6-iodo-7-(methyloxy)-4-quinazolinamine (2.1 g,4.5 mmol), 2-methyl-2-propanethiol (483 mg, 5.35 mmol), Et₃N (1.9 mL,13.4 mmol) in DMF (5 mL) was added Pd(Ph₃P)₄ (516 mg, 0.45 mmol). Thereaction mixture was stirred at 90-100° C. for 1 h. Most of DMF wasremoved in vacuo. The crude material was triturated with MeOH. The redsolid was filtered and washed with Et₂O to provide 1.7 g of the titlecompound as an off white solid (92%, 96% pure). MS: m/z: 397 [M+H]⁺.

Preparation 2N-(6-(tert-Butylsulfonyl)-7-methoxyquinazolin-4-yl)benzo[d]thiazol-5-amine

To a solution ofN-(6-(tert-butylthio)-7-methoxyquinazolin-4-yl)benzo[d]thiazol-5-amine(1.0 g, 2.5 mmol) in THF (20 mL) and water (2 mL) was added oxone (3.1g, 5.0 mmol). The reaction mixture was stirred at rt for 8 h. Satd. aq.NaHCO₃ was added to the reaction mixture to adjust to pH-7. The mixturewas extracted with EtOAc (100 mL×2) and CH₂Cl₂ (100 mL×2), dried overNa₂SO₄, and filtered. The solvent was removed in vacuo and crudematerial was purified by column chromatography (0 to 8% MeOH/CH₂Cl₂) toprovide 530 mg of the title compound (43.6%, 89% pure). MS: m/z: 429[M+H]⁺.

¹H NMR of N-(6-(tert-butylsulfonyl)-7-methoxyquinazolin-4-yl)benzo[d]thiazol-5-amine: (400 MHz,DMSO-d₆) δ 1.34 (s, 9H), 4.01 (s, 3H), 7.40 (s, 1H), 7.89 (dd, J=8.80,1.78 Hz, 1H), 8.17 (d, J=8.80 Hz, 1H), 8.59 (d, J=1.78 Hz, 1H), 8.64 (s,1H), 9.14 (s, 1H), 9.42 (s, 1H), 10.55 (s, 1H).

Preparation 34-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-ol

To a solution ofN-(6-(tert-butylsulfonyl)-7-methoxyquinazolin-4-yl)benzo[d]thiazol-5-amine(2.0 g, 4.7 mmol) in DMF (30 mL) was added sodium isopropylthiolate (2.7g, 28.0 mmol), and the solution was stirred at 150° C. for 1 h. Solventwas removed in vacuo. 1 N aq. HCl was added to reaction mixture toneutralize to pH=6. A yellow solid precipitated out, which was filteredand purified by column chromatography (0 to 5% MeOH/CH₂Cl₂) to provide1.5 g of the title compound (65.9%, 85% pure). MS: m/z: 415 [M+H]⁺.

¹H NMR of4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-ol:(400 MHz, DMSO-d₆) δ 1.15-1.46 (s, 9H), 7.21 (s, 1H), 7.89 (dd, J=8.72,1.78 Hz, 1H), 8.16 (d, J=8.72 Hz, 1H), 8.55 (s, 1H), 8.58 (d, J=1.78 Hz,1H), 9.07 (s, 1H), 9.42 (s, 1H), 10.47 (s, 1H), 11.45 (br. s., 1H).

Preparation 4 2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethanol

4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-ol (8.0g, 19.3 mmol) and K₂CO₃ (5.9 g, 42.5 mmol) were dissolved in 98 ml DMFand stirred 2 min before adding 2-bromoethanol (5.1 mL, 72.4 mmol). Themixture was heated for 3 h at 70° C., and then cooled to rt and stirredfor 18 h. Water (300 mL) was added, and the resulting solid was filteredand washed with water. The wet cake was slurried again in water andfiltered to give a tan solid. The solid was dissolved in hot EtOAc/MeOH(150 mL/50 mL) and cooled to rt to give a white solid precipitate whichwas filtered and dried under vacuum to give the product as a white solid(2.4 g). The resulting filtrate was evaporated to dryness, trituratedwith EtOAc, filtered, and dried to give a light brown solid (3.1 g). Thesolids were combined (5.5 g, 62% yield). Several batches of thismaterial were combined to give 15 g of input material. To this solid wasadded water (150 mL). The mixture was sonicated, and stirred for 15 minat rt. The solid was filtered and dried under vacuum at 70° C. for 3days to give the title compound as a solid (14.8 g, 98% recovery). MS:m/z: 459 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 1.36 (s, 9H), 3.81 (q,J=4.80 Hz, 2H), 4.28 (t, J=4.80 Hz, 2H), 4.81 (t, J=4.80 Hz, 1H), 7.41(s, 1H), 7.89 (d, J=8.40 Hz, 1H), 8.17 (d, J=8.40 Hz, 1H), 8.58 (s, 1H),8.63 (s, 1H), 9.14 (s, 1H), 9.42 (s, 1H), 10.55 (s, 1H).

Example 12-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate

2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethanol(4 g, 8.72 mmol) and Et₃N (1.824 mL, 13.08 mmol) were suspended (withheat gun to warm to dissolve as much as possible, not entirely solubleat this concentration) in triethylphosphate (40 mL) and cooled to 0° C.POCl₃ (1.220 mL, 13.08 mmol) was added dropwise slowly at 0° C. withvigorous stirring. The reaction was stirred at 0° C. for 1 hr untilcomplete. The reaction was quenched with water (4 mL) at 0° C. over 10min, suspended in DMSO-CH₃CN-50 mM sodium ammonium phosphate (pH=7)(ratio 1:1:8), then adjusted pH to 7 with NH₄OH to give completesolution, and purified by preparatory C18 HPLC (Luna C18, 10μ, 101×250mm column, 500 mL/min) using gradient 15-21% of CH₃CN in 50 mM sodiumammonium phosphate (pH=7) buffer. The fractions containing the desiredproduct (from multiple runs) were combined, adjusted pH to 3.6 withformic acid, and concentrated to 300 mL to give a yellow suspension. Thesuspension was readjusted pH to 3.6, chilled for 2 h in an ice bath;filtered off product, washed with 50 mL cold water and dried at 40° C.for 18 h on high vacuum to give a yellow solid,2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate (76% overall yield). ¹H NMR (400 MHz, DMSO-d₆) δppm 1.36 (s, 9H) 4.16-4.28 (m, 3H) 4.45 (t, J=4.55 Hz, 2H) 7.43 (s, 1H)7.89 (dd, J=8.72, 1.64 Hz, 1H) 8.17 (d, J=8.59 Hz, 1H) 8.58 (d, J=1.52Hz, 1H) 8.64 (s, 1H) 9.15 (s, 1H) 9.42 (s, 1H) 10.58 (br. s., 1H); MS(m/z) 539 (M+H⁺).

Example 22-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldisodium phosphate

2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate (95 mg, 0.176 mmol) was suspended in CH₃CN (2 mL)and water (2 mL), a solution of sodium bicarbonate (29.6 mg, 0.353 mmol)in water (1 mL) was added to give a clear solution which wasconcentrated to dryness on a rotary evaporator. The resultant residuewas triturated with CH₃CN and evaporated to dryness on a rotaryevaporator to give a white solid,2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldisodium phosphate (103 mg, 100%). ¹H NMR (400 MHz, D₂O) δ ppm 1.15 (s,9H) 3.94 (d, J=18.95 Hz, 4H) 6.31 (s, 1H) 6.82-7.02 (m, 2H) 7.37 (br.s., 1H) 7.76 (s, 1H) 7.90 (s, 1H) 8.70 (s, 1H); MS (m/z) 539(M−2Na⁺+3H⁺).

Example 3 Calcium (I)2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethylhydrogen phosphate trihydrate

Acetonitrile (11.0 mL) was added to2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate, (407.1 mg). The suspension was heated to 40° C.and Ca(OAc)₂ (0.5M solution in water, 0.5 equivalents) was added in 3equal portions (10 minutes apart) followed by seeding. The temperatureof the suspension was then cycled between 40° C. and 5° C. for ˜20hours. The crystalline solids were isolated by vacuum-filtration under anitrogen tent. The yield of the filtered solids was 90.1% (411.5 mg).The PXRD pattern of FIG. 1 was obtained after vacuum drying the solidsat 40° C. for 4 hours. Stoichiometry of the hemi-calcium salt wasconfirmed to be 1:0.5 (API: CI) by ICP-AES (3.8%, theoretical forhemi-Ca salt: 3.3%).

Seed crystals of this hydrated form of the hemi-calcium salt wereobtained from an analogous procedure conducted on a small scale, absentseeding.

Example 42-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate hydrochloride monohydrate

THF (11.0 mL) was added to2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate (401.0 mg). The suspension was heated to 40° C. andHCl acid (5M solution in water, 1.0 equivalent) was added in 3 equalportions (10 minutes apart) followed by seeding. The temperature of thesuspension was then cycled between 40° C. and 5° C. for ˜20 hours. Thecrystalline solids were isolated by vacuum-filtration under a nitrogentent. The yield of the filtered solids was 85.9% (379.4 mg). The PXRDpattern of FIG. 2 was obtained after vacuum drying the solids at 40° C.for 4 hours. Stoichiometry of this HCl salt was confirmed to be 1:1(API:CI) by ion chromatography for chloride content (5.99±0.42%,theoretical for HCl salt: 6.15%).

Seed crystals of this hydrated form of the HCl salt were obtained froman analogous procedure conducted on a small scale, absent seeding.

Example 5(S)-2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylbutanoate dihydrochloride a)(S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-((tert-butoxycarbonyl)amino)-3-methylbutanoate

(S)-2-((tert-Butoxycarbonyl)amino)-3-methylbutanoic acid (171 mg, 0.785mmol) and HATU (498 mg, 1.308 mmol) were dissolved in DMF (4 mL) at rt,i-Pr₂NEt (0.229 mL, 1.308 mmol) was added, stirring was continued for 15min followed by the addition of2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethanol(300 mg, 0.654 mmol) and DMAP (15.99 mg, 0.13 mmol). The reactionmixture was stirred for 16 hrs at rt, diluted with EtOAc (100 ml),washed with water, brine, dried over MgSO₄, and concentrated. Theresidue was purified on silica gel (40 g, 5% MeOH/DCM) to give(S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (387 mg, 90%). ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.87 (t, 6H) 1.36 (s, 9H) 1.38 (s, 9H)2.03-2.14 (m, 1H) 3.92 (dd, J=8.08, 6.06 Hz, 1H) 4.47 (d, J=10.86 Hz,4H) 7.14 (d, J=8.34 Hz, 1H) 7.44 (s, 1H) 7.89 (dd, J=8.59, 2.02 Hz, 1H)8.17 (d, J=8.59 Hz, 1H) 8.58 (d, J=2.02 Hz, 1H) 8.64 (s, 1H) 9.16 (s,1H) 9.43 (s, 1H) 10.57 (s, 1H); MS (m/z) 658 (M+H⁺).

b)(S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylbutanoate dihydrochloride

HCl in 1,4-dioxane (4.33 mL, 17.33 mmol) was added to a vial containing(S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-((tert-butoxy carbonyl)amino)-3-methylbutanoate (380 mg, 0.578 mmol),the suspension was stirred at rt for 1 hr, concentrated, the solid wascollected by filtration, washed with EtOAc, and dried under high vacuumfor 16 hrs to give an off-white solid,(5)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylbutanoate dihydrochloride (326 mg, 89%). ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.99 (d, J=7.07 Hz, 6H) 1.37 (s, 9H) 2.26 (dd, 1H)3.91 (d, J=5.31 Hz, 1H) 4.60 (d, J=11.87 Hz, 4H) 7.71 (s, 1H) 7.78 (dd,J=8.72, 1.64 Hz, 1H) 8.30 (d, J=8.59 Hz, 1H) 8.44 (d, J=1.77 Hz, 1H)8.56 (br. s., 3H) 8.95 (s, 1H) 9.34 (s, 1H) 9.50 (s, 1H) 12.09 (br. s.,1H); MS (m/z) 558 (M+H⁺).

The following compound was prepared in the same manner using(R)-2-((tert-butoxy carbonyl)amino)-3-methylbutanoic acid

Example 6(R)-2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylbutanoate, dihydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.99 (d, 6H) 1.37 (s, 9H) 2.21-2.32 (m,1H) 3.90 (d, J=4.80 Hz, 1H) 4.48-4.69 (m, 4H) 7.69 (s, 1H) 7.80 (dd,J=8.72, 1.89 Hz, 1 H) 8.28 (d, J=8.59 Hz, 1H) 8.46 (d, J=2.02 Hz, 1H)8.58 (d, J=3.79 Hz, 3H) 8.91 (s, 1H) 9.32 (s, 1H) 9.49 (s, 1H) 11.88(br. s., 2H); MS (m/z) 558 (M+H⁺).

Example 7(2S,3S)-2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylpentanoate

(2S,3S)-2-((tert-Butoxycarbonyl)amino)-3-methylpentanoic acid (60.5 mg,0.262 mmol) and HATU (166 mg, 0.436 mmol) were dissolved in DMF (2 mL)and cooled at 23° C., DIEA (0.076 mL, 0.436 mmol) and DMAP (5.33 mg,0.044 mmol) were added, stirring was continued for 30 min followed byaddition of2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethanol(100 mg, 0.218 mmol). The reaction mixture was stirred for 3 days at rt,then heated at 50° C. for 20 hrs, reaction was not complete.

A solution of (2S,3S)-2-((tert-butoxycarbonyl)amino)-3-methylpentanoicacid (121 mg, 0.52 mmol) and HATU (332 mg, 0.87 mmol) and DIEA (0.15 mL,0.87 mmol) in DMF (1 ml) was prepared and stirred for 15 min before itwas added to the above reaction mixture. The resulting reaction mixturewas heated at 50° C. for 4 hrs, purified on Gilson HPLC (100×150 mm RPSunfire column) using 20-70% ACN/water/TFA (0.05%). The fractionscontaining the desired product were combined, concentrated on rotovap.The residue was dissolved in dioxane (1 ml), then HCl (1 ml, 4M indioxane) was added at rt, and the resulting mixture was stirred for 1 hruntil all starting material converted to desired product. The reactionmixture was concentrated, partitioned between EtOAc and aqueous sodiumbicarbonate, the organic layer was separated, washed with brine, dried(MgSO₄), and concentrated to give a white solid(2S,3S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylpentanoate (74 mg, 0.126 mmol, 57.6% yield). ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.78-0.83 (m, 3H) 0.85 (d, J=6.82 Hz, 3H) 1.05-1.21(m, 1H) 1.35 (s, 9H) 1.43 (ddd, J=13.45, 7.52, 4.29 Hz, 1H) 1.57-1.70(m, 1H) 3.15-3.23 (m, 1H) 4.34-4.57 (m, 4H) 7.44 (s, 1H) 7.89 (dd,J=8.72, 1.89 Hz, 1H) 8.17 (d, J=8.59 Hz, 1H) 8.58 (d, J=1.77 Hz, 1H)8.64 (s, 1H) 9.15 (s, 1H) 9.42 (s, 1H) 10.56 (s, 1H); MS (m/z) 572(M+H⁺).

Example 8 Biological Assays

In vivo Assay (I)

The efficacy of RIP2 inhibitors may be evaluated in vivo in rodents.Intraperitoneal (i.p.) or intravenous (i.v.) administration of L18-MDPin mice has been shown to induce an inflammatory response throughactivation of the NOD2 signaling pathway (Rosenweig, H. L., et al. 2008.Journal of Leukocyte Biology 84:529-536). The level of the inflammatoryresponse in the L18-MDP treated mice/rats is monitored usingconventional techniques by measuring increases in cytokine levels (IL8,TNFα, IL6 and IL-1β) in serum and/or peritoneal lavage fluid and bymeasuring neutrophil influx into the peritoneal space (when L18-MDP isdosed i.p.). Inhibition of the L18-MDP induced inflammatory response intreated rodents may be shown by orally pre-dosing with test compounds,then measuring and comparing cytokine levels (IL8, TNFα, IL6 and IL-1β)in serum and/or peritoneal lavage fluid and neutrophil influx into theperitoneal space (when L18-MDP is dosed i.p.) using conventionaltechniques.

Rats were orally pre-dosed with the compound,2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethanol,at a dose of 2 mg/kg (8 rats) and with prednisolone (8 rats, used as apositive control), followed by dosing with L18-MDP (50 μg/rat) 0.25h/min after pre-dosing. Combined cytokine levels (IL8, TNFα, IL6 andIL-1β) in whole blood samples taken from the rats in this study weremeasured using an antibody based detection (Meso-Scale Discoveryplatform). The combined cytokine response was calculated as the averagedresponse for the 4 cytokines measured relative to the response observedin the vehicle-treated mice, and are depicted in FIG. 3 as themean±standard error of the mean (n=8 rats/group).

In vivo Assay (II)

2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate was orally administered at a dose equivalent to 2mg/kg of2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethanolto a series of test animals. Rats (n=2) and dogs (n=3) were administered2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate, whereas minipigs (male Göttingen minipigs (n=3))were administered2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldisodium phosphate. Blood samples were taken from each test animal atintervals between 0 to 24 hrs (25 hrs in dog) after administration. Theconcentration2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethanolin each sample was determined by LC/MS. The average blood concentrationsof2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethanolin each test species, following oral administration of2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate or disodium phosphate are shown in FIG. 4.

The half life (T_(1/2)) of2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldihydrogen phosphate was determined to be 15 min in rat and 5 min indog. The half life (T₁₁₂) of2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyldisodium phosphate was determined to be 26 min in minipig.

Pharmaceutical Compositions Example A

Tablets are prepared using conventional methods and are formulated asfollows:

Ingredient Amount per tablet Compound  5 mg Microcrystalline cellulose100 mg Lactose 100 mg Sodium starch glycollate  30 mg Magnesium stearate 2 mg Total 237 mg

Example B

Capsules are prepared using conventional methods and are formulated asfollows:

Ingredient Amount per tablet Compound  15 mg Dried starch 178 mgMagnesium stearate  2 mg Total 195 mg

What is claimed is:
 1. A compound which is:

or a pharmaceutically acceptable salt thereof.
 2. A compound which is(S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylbutanoate.
 3. The compound, or pharmaceuticallyacceptable salt thereof, according to claim 1, which is thepharmaceutically acceptable salt of said compound.
 4. The compound, orpharmaceutically acceptable salt thereof, according to claim 3, whereinthe pharmaceutically acceptable salt is a hydrochloride salt.
 5. Acompound which is(S)-2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl2-amino-3-methylbutanoate dihydrochloride.
 6. A pharmaceuticalcomposition comprising the compound, or pharmaceutically acceptable saltthereof, according to claim 1, and a pharmaceutically acceptableexcipient.
 7. A method of treating a disease mediated by inhibition ofRIP2 kinase comprising administering a therapeutically effective amountof the compound, or pharmaceutically acceptable salt thereof, accordingto claim 1, to a human in need thereof, wherein the disease mediated byinhibition of RIP2 kinase is selected from uveitis, dermatitis, acutelung injury, type 2 diabetes mellitus, arthritis, rheumatoid arthritis,ulcerative colitis, Crohn's disease, early-onset inflammatory boweldisease, extraintestinal inflammatory bowel disease, prevention ofischemia reperfusion injury in solid organ transplant, non-alcoholsteatohepatitis, autoimmune hepatitis, asthma, systemic lupuserythematosus, multiple sclerosis, sarcoidosis, Blausyndrome/early-onset sarcoidosis, Wegner's granulomatosis, andinterstitial pulmonary disease.
 8. The method according to claim 7,wherein the disease is selected from uveitis, Blau Syndrome, early-onsetsarcoidosis, ulcerative colitis, Crohn's disease, Wegener'sgranulamatosis and sarcoidosis.
 9. The method according to claim 7,wherein the disease is Crohn's disease.
 10. The method according toclaim 7, wherein the disease is ulcerative colitis.
 11. The methodaccording to claim 7, wherein the disease is Blau syndrome.
 12. Themethod according to claim 7, wherein the disease is rheumatoidarthritis.